Variations or mutations in DNA are directly related to almost all human phenotypic traits and diseases, including infectious disease, cancer, inherited disorders, and autoimmune disorders. The most common type of DNA variation is a single nucleotide polymorphism (SNP), which is a base pair substitution at a single position in the genome. It has been estimated that SNPs account for the bulk of the DNA sequence difference between humans (Patil, N. et al., Science, 294:1719 (2001)). Blocks of such SNPs in close physical proximity in the genome are often genetically linked, resulting in reduced genetic variability and defining a limited number of “SNP haplotypes”, each of which reflects descent from a single, ancient chromosome (Fullerton, S. M., et al., Am. J. Hum. Genet. 67: 881 (2000)).
Patterns of human DNA sequence variation (haplotypes) defined by SNPs have important implications for identifying associations between phenotypic traits and genetic loci. However, the complexity of local haplotype structure in the human genome and the distance over which individual haplotype blocks extend is poorly defined, with some haplotype blocks extending for only a few kilobases and others extending for more than 100 kilobases (Patil, N. et al., Science, 294:1719 (2001)). These findings suggest that any comprehensive description of the haplotype structure of the human genome, defined by common SNPs, will require empirical analysis of a dense set of SNPs in many independent copies of the human genome. As a first step toward achieving this goal, high-density oligonucleotide arrays were used to identify a large fraction of all human chromosome 21 SNPs and to analyze the haplotype structure they define (Patil, N. et al., Science, 294:1719 (2001).
The haplotype structure of the human genome is of great value for various applications. For example, specific regions of interest may be further analyzed to associate SNPs in haplotype blocks with phenotypic traits—for example, disease susceptibility or resistance, a predisposition to a genetic disorder, or drug response—and this information may be invaluable in understanding the biological basis for the trait as well as identifying candidate genes useful in the development of therapeutics and diagnostics. The haplotype structure may also be used to identify individuals from biological samples, for example, in paternity testing or criminal investigations.
One such region of interest is found on the long arm of chromosome 21. This region contains two genes, KCNE1 and KCNE2, both of which code for proteins that are subunits of cardiac potassium channels, key components of the electrical system of the heart. Malfunction of these channels can cause abnormalities in the repolarization of the heart resulting in less efficient pumping of oxygenated blood through the body. Long QT Syndrome (LQTS), a familial and potentially fatal disorder of the electrical system of the heart, is also caused by malfunction of the cardiac potassium ion channels, which can lead to cardiac arrhythmia that may degenerate into ventricular tachycardia and even result in death. Currently, there is no quick and reliable method of identifying individuals with malfunctions of these potassium ion channels or a predisposition to LQTS.